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SA-β-Galactosidase-Based Screening Assay for the Identification of Senotherapeutic Drugs
Published on: June 28, 2019
Therapeutic targeting of senescent cells in the CNS
Markus Riessland1,2, Methodios Ximerakis3, Andrew A Jarjour4
1Department of Neurobiology and Behavior, Stony Brook University, Stony Brook, NY, USA.
Abstract:
Senescent cells accumulate throughout the body with advanced age, diseases and chronic conditions. They negatively impact health and function of multiple systems, including the central nervous system (CNS). Therapies that target senescent cells, broadly referred to as senotherapeutics, recently emerged as potentially important treatment strategies for the CNS. Promising therapeutic approaches involve clearing senescent cells by disarming their pro-survival pathways with 'senolytics'; or dampening their toxic senescence-associated secretory phenotype (SASP) using 'senomorphics'. Following the pioneering discovery of first-generation senolytics dasatinib and quercetin, dozens of additional therapies have been identified, and several promising targets are under investigation. Although potentially transformative, senotherapies are still in early stages and require thorough testing to ensure reliable target engagement, specificity, safety and efficacy. The limited brain penetrance and potential toxic side effects of CNS-acting senotherapeutics pose challenges for drug development and translation to the clinic. This Review assesses the potential impact of senotherapeutics for neurological conditions by summarizing preclinical evidence, innovative methods for target and biomarker identification, academic and industry drug development pipelines and progress in clinical trials.
Insights
Senescent cells impact the central nervous system. Senotherapeutics, including senolytics and senomorphics, show promise for neurological conditions but require further safety and efficacy testing.
Area of Science:
- Gerontology
- Neuroscience
- Pharmacology
Background:
- Senescent cells accumulate with age and disease, negatively affecting central nervous system (CNS) health.
- Senotherapeutics, targeting senescent cells, are emerging as potential treatments for neurological disorders.
- Current approaches include senolytics to clear senescent cells and senomorphics to reduce their harmful secretions.
Purpose of the Study:
- To review the potential impact of senotherapeutics on neurological conditions.
- To summarize preclinical evidence and drug development pipelines for CNS-acting senotherapies.
- To highlight challenges and progress in clinical trials for senotherapeutics in neurological diseases.
Main Methods:
- Literature review of preclinical evidence on senotherapeutics for CNS disorders.
- Assessment of innovative methods for target and biomarker identification.
- Analysis of academic and industry drug development pipelines and clinical trial progress.
Main Results:
- Dozens of senolytic and senomorphic therapies have been identified beyond initial agents like dasatinib and quercetin.
- Promising targets are under investigation, with ongoing development in both academic and industry settings.
- Early-stage clinical trials are underway, but challenges in brain penetrance and safety remain.
Conclusions:
- Senotherapeutics hold significant potential for treating neurological conditions by targeting cellular senescence.
- Rigorous testing is crucial to ensure the safety, efficacy, and target engagement of these novel therapies.
- Overcoming challenges in drug delivery and potential side effects is key for successful clinical translation.
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